Nature Communications (Jun 2023)
Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2
- Katherine U. Gaynor,
- Marina Vaysburd,
- Maximilian A. J. Harman,
- Anna Albecka,
- Phillip Jeffrey,
- Paul Beswick,
- Guido Papa,
- Liuhong Chen,
- Donna Mallery,
- Brian McGuinness,
- Katerine Van Rietschoten,
- Steven Stanway,
- Paul Brear,
- Aleksei Lulla,
- Katarzyna Ciazynska,
- Veronica T. Chang,
- Jo Sharp,
- Megan Neary,
- Helen Box,
- Jo Herriott,
- Edyta Kijak,
- Lee Tatham,
- Eleanor G. Bentley,
- Parul Sharma,
- Adam Kirby,
- Ximeng Han,
- James P. Stewart,
- Andrew Owen,
- John A. G. Briggs,
- Marko Hyvönen,
- Michael J. Skynner,
- Leo C. James
Affiliations
- Katherine U. Gaynor
- Bicycle Therapeutics, Portway Building, Granta Park
- Marina Vaysburd
- MRC Laboratory of Molecular Biology, Francis Crick Avenue
- Maximilian A. J. Harman
- Bicycle Therapeutics, Portway Building, Granta Park
- Anna Albecka
- MRC Laboratory of Molecular Biology, Francis Crick Avenue
- Phillip Jeffrey
- Bicycle Therapeutics, Portway Building, Granta Park
- Paul Beswick
- Bicycle Therapeutics, Portway Building, Granta Park
- Guido Papa
- MRC Laboratory of Molecular Biology, Francis Crick Avenue
- Liuhong Chen
- Bicycle Therapeutics, Portway Building, Granta Park
- Donna Mallery
- MRC Laboratory of Molecular Biology, Francis Crick Avenue
- Brian McGuinness
- Bicycle Therapeutics, Portway Building, Granta Park
- Katerine Van Rietschoten
- Bicycle Therapeutics, Portway Building, Granta Park
- Steven Stanway
- Bicycle Therapeutics, Portway Building, Granta Park
- Paul Brear
- Department of Biochemistry, University of Cambridge
- Aleksei Lulla
- Department of Biochemistry, University of Cambridge
- Katarzyna Ciazynska
- MRC Laboratory of Molecular Biology, Francis Crick Avenue
- Veronica T. Chang
- MRC Laboratory of Molecular Biology, Francis Crick Avenue
- Jo Sharp
- University of Liverpool
- Megan Neary
- University of Liverpool
- Helen Box
- University of Liverpool
- Jo Herriott
- University of Liverpool
- Edyta Kijak
- University of Liverpool
- Lee Tatham
- University of Liverpool
- Eleanor G. Bentley
- University of Liverpool
- Parul Sharma
- University of Liverpool
- Adam Kirby
- University of Liverpool
- Ximeng Han
- University of Liverpool
- James P. Stewart
- University of Liverpool
- Andrew Owen
- University of Liverpool
- John A. G. Briggs
- MRC Laboratory of Molecular Biology, Francis Crick Avenue
- Marko Hyvönen
- Department of Biochemistry, University of Cambridge
- Michael J. Skynner
- Bicycle Therapeutics, Portway Building, Granta Park
- Leo C. James
- MRC Laboratory of Molecular Biology, Francis Crick Avenue
- DOI
- https://doi.org/10.1038/s41467-023-39158-1
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 15
Abstract
Abstract COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles’ inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses.
